Mechanistic study of the tandem intramolecular (4+2)/intermolecular (3+2) cycloaddition reactions for the formation of polyaza- and polyisoxazolidine-steroids

The ability to construct molecules with potential applications in biomedicine via efficient and selective molecular design and syntheses hinges on a thorough understanding of underlying reaction mechanisms. The biological importance of steroids and related heterocyclic compounds are well known but theoretical studies aimed at delineating reaction mechanisms to complement efforts of experimentalists are lacking. Herein, we report an extensive theoretical study on the regio-, stereo-, and enantio-selectivity of the tandem sequential intramolecular (4 + 2)/intermolecular (3 + 2) cycloaddition reaction of (E)-3-(2-[furan-2-ylmethoxy]phenyl)acrylate derivatives (R1) and azides (R3 and R3 ') as well as nitrones (R2) for the formation of steroids. In the reaction of R1 and the azide derivatives R3 and R3 ', the intramolecular (4 + 2) cycloaddition of R1 is the rate-determining step (rds). The reaction is also found to be very selective. Reaction of electron-withdrawing groups-substituted R1 with R3 is found to generally increase the barrier of the rds except bromine whiles electron-donating groups are found to generally decrease the activation energies of the rds. Subsequently, we report a novel reaction of R1 with cyclic nitrone (R2), which compares favorably with the azide reaction. Results from the global reactivity descriptors are in good agreement with the activation barrier trends. All the considered reactions in this study are found to be kinetically driven.